16-1999991-G-C

Position:

• chr16-1999991-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000562103.2(ZNF598):​c.1558C>G​(p.Pro520Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF598 ENST00000562103.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.662

Genes affected

ZNF598 (HGNC:28079): (zinc finger protein 598, E3 ubiquitin ligase) Zinc-finger proteins bind nucleic acids and play important roles in various cellular functions, including cell proliferation, differentiation, and apoptosis. This protein and Grb10-interacting GYF protein 2 have been identified as a components of the mammalian 4EHP (m4EHP) complex. The complex is thought to function as a translation repressor in embryonic development. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04209611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF598	NM_178167.5	c.1558C>G	p.Pro520Ala	missense_variant	11/14	ENST00000710288.1	NP_835461.2
ZNF598	NM_001405665.1	c.1540C>G	p.Pro514Ala	missense_variant	11/14		NP_001392594.1
ZNF598	NM_001405664.1	c.1588C>G	p.Pro530Ala	missense_variant	11/14		NP_001392593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF598	ENST00000562103.2	c.1558C>G	p.Pro520Ala	missense_variant	11/14	1		ENSP00000455308	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000540 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.1558C>G (p.P520A) alteration is located in exon 9 (coding exon 9) of the ZNF598 gene. This alteration results from a C to G substitution at nucleotide position 1558, causing the proline (P) at amino acid position 520 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.091
DANN	Benign	0.42
DEOGEN2	Benign	0.016	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.47	.;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N;N
Sift	Benign	0.84	T;T
Sift4G	Uncertain	0.040	D;D
Vest4		0.052
MVP		0.17
ClinPred		0.033	T
GERP RS		-5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs369313423; hg19: chr16-2049992;